3-arylisocoumarins with amino-acid fragments

Article abstract of DOI:10.1007/s10600-014-1042-5

New amino-acid derivatives of 3-arylisocoumarins were prepared via acylation of the amine groups of natural amino acids by phenoxyacetic acids containing an isocoumarin substituent on the benzene ring.

Full text of DOI:10.1007/s10600-014-1042-5

Chemistry of Natural Compounds, Vol. 50, No. 4, September, 2014 [Russian original No. 4, July–August, 2014]
3
-ARYLISOCOUMARINS WITH AMINO-ACID FRAGMENTS
*
S. V. Shilin, O. V. Shablykina, V. V. Ishchenko, and V. P. Khilya
New amino-acid derivatives of 3-arylisocoumarins were prepared via acylation of the amine groups of
natural amino acids by phenoxyacetic acids containing an isocoumarin substituent on the benzene ring.
Keywords: [4-(1-oxo-1H-isochromen-3-yl)phenoxy]acetic acid, [2-(1-oxo-1H-isochromen-3-yl)-4-
methylphenoxy]acetic acid, N-hydroxysuccinimide, activated ester, amino acid.
Interest in isocoumarins has risen consistently since the first mention of natural [1] and synthetic [2] compounds with
this core because they are widely distributed in nature and possess high biological activity. The variety of modifications of this
heterocyclic system was apparent after the isolation and identification of natural isocoumarins and dihydroisocoumarins from
plants and microorganisms.
Plant isocoumarins can include both simple molecules and complicated polycyclic structures in both the free and
bound state. For example, the heterocyclic isocoumarin ring can be found in glycosides [homalicin (1) and dihydrohomalicin
(
2)] and as amino-acid derivatives of active functional groups such as ochratoxin A (3) [3] and amicoumacin B (4) [4]. The
antibacterial and gastric-protection activities of a group of amicoumacins isolated from plant material were especially high [4,
]. This confirmed that research on the design of natural compound analogs that combine an isocoumarin core with an amino
5
acid was important and urgent.
O
O
OH
O
COOH
O
O
O
OH
Cl
O
O
H H
N
OGlc
OGlc
COOH
N
H
O
O
OOH
1
2
3
4
_
O
O
1. OH
O
O
+
COOH
O
+
2
. H
a
H
O
O
OH
OCH
2
COOCH
3
OCH
2
COOH
2
OCH COOH
R
R
R
R
5
, 6
7, 8
5
: 4-OH, R = H; 6: 2-OH, R = CH ; 7: 4-OCH COOH, R = H; 8: 2-OCH COOH, R = CH
3 2 2 3
a. BrCH COOCH , K CO , acetone
2
3
2
3
Herein we present results from modification of homalicin aglycon analogs, i.e., 3-(4-hydroxyphenyl)isocoumarin (5)
and 3-(2-hydroxy-5-methylphenyl)isocoumarin (6), at the active hydroxyl by various natural amino acids. The linker was
hydroxyacetic acid.
Isocoumarin derivatives 5 and 6 were alkylated by chloroacetic acid ester with subsequent hydrolysis of the ester [6]
to obtain 7 and 8 with a carboxylic acid that was capable of reacting with the amino-acid NH group.
2
Taras Shevchenko Kiev National University, Ul. Vladimirskaya, 64/13, 01601, Kiev, Ukraine, e-mail:
shablykina@ukr.net. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2014, pp. 554–558. Original
article submitted May 12, 2014.
638
0009-3130/14/5004-0638 ©2014 Springer Science+Business Media New York

TABLE 1. Yields and Melting Points of 11 and 12
Amino acid
Compound
mp, ꢀC
Yield, %
Compound
mp, ꢀC
Yield, %
Glycine
Alanine
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
234–235
238–239
197–198
204–206
195–196
187–188
198–199
223–224
238–239
233–234
86
71
70
75
73
84
68
78
76
49
79
85
71
72
49
12a
12b
161–162
187–188
57
71
ꢁ-Aminobutyric acid
Valine
Leucine
Norleucine
Proline
ꢂ-Alanine
Phenylalanine
Tryptophan
Methionine
Aspartic acid
Asparagine
Glutamic acid
Citrulline
12e
81–82
84
12j
12k
209–210
131–132
65
25
1
63–165
211–213
38–139
209–211
84–186
1
12m
116–117
88
1
The amino acid was introduced into the molecule using the activated-ester method that is popular in peptide synthesis
[
7, 8]. In our instance, amino acids were reacted with the N-hydroxysuccinimide (SucOH) esters of 7 and 8. The high
reactivity of the SucOH esters allowed the reaction to be carried out under mild conditions and avoided racemization.
SucOH esters 9 and 10 were prepared by reaction of 7 and 8 with SucOH in anhydrous dioxane at room temperature
with dicyclohexylcarbodiimide (DCC) as the condensing agent. Ester formation was monitored by TLC. When the reaction
was finished, an aqueous solution of the sodium salt of the appropriate amino acid was added directly to the reaction mixture
without isolating the ester. Thus, the final acylation of the amino acid occurred in H O–dioxane (1:1). Products 11 and 12
2
were isolated by acidolysis of the reaction mixture.
Het
OCH COOH
2
H C
3
OCH COOH
2
7
8
Het
Het
O
O
3
H C
O
O
O
Suc
Het
O Suc
9
10
2
'
4'
2
'
Het
O
'
O
H
3
C
O
O
4
COOH
R
COOH
6
'
6'
N
N
Het
H
H
R
1
1a-f, j-o
12a,b,e,j,k,m
O
8
5
1
7
6
O
Het
O
O
Het
O
O
Het =
3
4
N
N
H
HOOC
COOH
1
1g
11b
1
1a, 12a: R = H; 11b, 12b: R = CH ; 11c: R = C H ; 11d: R = CH(CH ) ; 11e,12e: R = CH CH(CH )
3 2 5 3 2 2 3 2
1
1f: R = (CH2 ) CH ; 11i: R = CH Ph; 11j, 12j: R = CH (indol-3-yl); 11k, 12k: R = CH CH SCH
2 3 3 2 2 2 2 3
1
1l: R = CH COH; 11m, 12m: R = CH CONH ; 11n: R = CH CH COOH; 11o: R = (CH ) NHCONH
2 2 2 2 2 2 3 2
Ester 9 was formed from acid 7 in about 2 h, like for the reaction with the amino acid. Amino-acid derivatives
11a–i and –k–n were obtained in high yields (68–86%) (Table 1). The yields of the tryptophan and citrulline derivatives 11j
and –o were slightly lower (49%).
639

Asignificant difference in the reactivities of 7 and 8 that was not noted previously was observed during the preparation
of ester 10. In this instance, it was most probably due to steric hindrance. The reaction of SucOH and 8 required at least 96 h
although the overall yields of 12b, –e, –j, and –m were greater than the corresponding compounds 11b, –e, –j, and –m
(
Table 1). The yield of the amino-acid derivative decreased significantly only for methionine (25%).
PMR spectra of 11 and 12 (see Experimental) exhibited a combination of proton resonances that was characteristic of
a 3-arylisocoumarin (in particular, the H8 resonance was typically a doublet among aromatic protons located at the weakest
field of 8.1–8.2 ppm) and the corresponding N-substituted amino acid in addition to the resonance of the hydroxyacetic acid
methylene protons (4.6 ppm). The IR and UV spectra (see Experimental) were characteristic for this class of compounds and
confirmed their structures.
Thus, new 3-arylisocoumarin derivatives with an amino-acid fragment were prepared by successful modification of
isocoumarinyl phenoxyacetic acids via reaction with activated esters and various natural amino acids. The effectiveness of
this reaction depended more on the activity and steric accessibility of the carboxylic acid than on the nature of the amino acid.
The activated-ester method gave good results, even for slow reactions, especially considering the mild conditions and the
ability to use a rather wide range of amino acids.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck 60 F254 plates using CHCl –MeOH
3
(
9:1). Melting points were measured on a Kofler apparatus. PMR spectra were measured in DMSO-d –CCl (1:1) with TMS
6
4
internal standard on a Varian Mercury-400 spectrometer; IR spectra, in KBr on a PerkinElmer BXII spectrometer; UV spectra,
in EtOH on a Shimadzu UV-3100 spectrometer. Elemental analyses of all compounds were obtained using a Vario Micro
Cube instrument and agreed with those calculated.
The synthesis method, yields, melting points, elemental analyses, and PMR spectra of 7 and 8 were published before [6].
–
1
[
2-(1-Oxo-1H-isochromen-3-yl)-4-methylphenoxy]aceticAcid (7). IR spectrum (ꢃ, cm ): 3424, 3068, 3003, 2928,
–
1
–1
2
(
588, 1724, 1633, 1605, 1517, 1484, 1420, 1254, 1190, 1076, 823. UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ): 348 (11900), 304
24100), 250 (11200).
4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetic Acid (8). IR spectrum (ꢃ, cm ): 3449, 3113, 2916, 1758, 1670,
–
1
[
–
1
–1
1
619, 1507, 1480, 1436, 1212, 1148, 1114, 1074. UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ): 347 (12100), 320 (12400), 297
(
16000).
General Method for Synthesizing Amino-acid Derivatives (11 and 12). A solution of acid 7 or 8 (2 mmol) and
SucOH (0.26 g, 2.2 mmol) in anhydrous dioxane (20 mL) at room temperature was stirred vigorously, treated with DCC
0.46 g, 2.2 mmol), and stirred at room temperature for 2 h (7) or 96 h (8) to form the ester (course of reaction monitored by
TLC). The resulting activated ester was treated with a solution of the appropriate amino acid (2.2 mmol) and NaHCO3
0.28 g, 3.3 mmol) in H O (20 mL) and stirred at room temperature for 2 h. The course of the reaction was monitored by TLC.
(
(
2
The precipitate of dicyclohexylurea was filtered off. The filtrate was poured into H O (100 mL) and acidified with dilute HCl
2
until weakly acidic. The resulting precipitate was filtered off and recrystallized from i-PrOH.
–1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}glycine (11a). C H NO . IR spectrum (ꢃ, cm ): 3394, 3086,
19
15
6
2
933, 2863, 2753, 2510, 1719, 1630, 1552, 1514, 1483, 1442, 1293, 1252, 1237, 1184, 1067, 1013, 828. UV spectrum (ꢄmax,
–
1
–1
1
nm, ꢅ, Ì ·cm ): 348 (11700), 304 (23700), 250 (11200). Í NMR spectrum* (ꢆ, ppm, J/Hz): 3.82 (2Í, br.d, J = 4.8,
CH ÑÎÎÍ), 4.58 (2Í, s, ÑÍ Î-4ꢇ), 7.10 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.24 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6, Í-7), 7.61 (1Í, d,
2
2
J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.86 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.14 (1Í, d, J = 7.6, Í-8), 8.30 (1Í, br.t, J = 4.8, NH).
–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}alanine (11b). C H NO . IR spectrum (ꢃ, cm ): 3402,
2
0
17
6
3
092, 3064, 2922, 2543, 1726, 1638, 1547, 1514, 1440, 1287, 1254, 1235, 1183, 1062, 1014, 827. UV spectrum (ꢄmax, nm,
–1
–1
1
ꢅ, Ì ·cm ): 345 (12300), 304 (24900), 250 (11900). Í NMR spectrum* (ꢆ, ppm, J/Hz): 1.38 (3Í, d, J = 6.8, CH(CH )ÑÎÎÍ),
3
4
.32–4.37 (1Í, m, CH(CH )ÑÎÎÍ), 4.56 (2Í, s, ÑÍ Î-4ꢇ), 7.09 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.22 (1Í, s, Í-4), 7.50 (1Í, t, J = 7.6,
3 2
Í-7), 7.61 (1Í, d, J = 7.6, Í-5), 7.76 (1Í, t, J = 7.6, Í-6), 7.86 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.13–8.18 (2Í, m, NH, Í-8).
2
-(N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}amino)butanoic Acid (11c). C H NO . IR spectrum
2
1
19
6
–
1
(
ꢃ, cm ): 3378, 3083, 2970, 2936, 2762, 2543, 1723, 1635, 1543, 1513, 1235, 1185, 1070, 830. UV spectrum (ꢄmax, nm,
–
1
–1
1
ꢅ, Ì ·cm ): 345 (12500), 303 (25300), 250 (12000). Í NMR spectrum (ꢆ, ppm, J/Hz): 0.95 (3Í, t, J = 6.8, CH(ÑÍ CH )ÑÎÎÍ),
2
3
ꢈꢈꢈꢈꢈꢈ
ꢉ
The amino-acid COOH proton resonance in PMR spectra of was not observed because of exchange.
640

1
.72 (1Í, m, CH(ÑÍ CH )ÑÎÎÍ), 1.86 (1Í, m, CH(ÑÍ CH )ÑÎÎÍ), 4.26 (1Í, m, CH(ÑÍ CH )ÑÎÎÍ), 4.59 (2Í, s,
2 3 2 3 2 3
ÑÍ Î-4ꢇ), 7.08 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.22 (1Í, s, Í-4), 7.50 (1Í, t, J = 7.6, Í-7), 7.61 (1Í, d, J = 7.6, Í-5), 7.76 (1Í, t,
2
J = 7.6, Í-6), 7.85 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.09 (1Í, d, J = 7.6, NH), 8.13 (1Í, d, J = 7.6, Í-8), 12.62 (1Í, br.s, ÑÎÎÍ).
–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}valine (11d). C H NO . IR spectrum (ꢃ, cm ): 3390, 2967,
2
2
21
6
–
1
–1
2
(
878, 2548, 1719, 1635, 1611, 1541, 1512, 1435, 1422, 1237, 1184, 1073, 827. UV spectrum (ꢄ , nm, ꢅ, Ì ·cm ): 346
12900), 304 (26000), 251 (12400). Í NMR spectrum* (ꢆ, ppm, J/Hz): 0.93 (6Í, m, CH(ÑÍ(CH ) )ÑÎÎÍ), 2.16 (1Í, m,
max
1
3
2
CH(ÑÍ(CH ) )ÑÎÎÍ), 4.27 (1Í, m, CH(ÑÍ(CH ) )ÑÎÎÍ), 4.64 (2Í, s, ÑÍ Î-4ꢇ), 7.07 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.24 (1Í,
3
2
3 2
2
s, Í-4), 7.51 (1Í, t, J = 7.6, Í-7), 7.62 (1Í, d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.85 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 7.94 (1Í,
br.d, J = 7.6, NH), 8.14 (1Í, d, J = 7.6, Í-8).
–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}leucine (11e). C H NO . IR spectrum (ꢃ, cm ): 3384, 3084,
23
23
6
–1
–1
2
3
962, 2872, 2511, 1724, 1636, 1611, 1543, 1514, 1438, 1236, 1069, 830. UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ): 344 (13200),
04 (26600), 251 (12600). Í NMR spectrum (ꢆ, ppm, J/Hz): 0.91 (6Í, m, CH(ÑÍ ÑÍ(CH ) )ÑÎÎÍ), 1.55–1.57 (3Í, m,
1
2
3 2
CH(ÑÍ ÑÍ(CH ) )ÑÎÎÍ), 4.33 (3Í, m, CH(ÑÍ ÑÍ(CH ) )-ÑÎÎÍ), 4.57 (2Í, s, ÑÍ Î-4ꢇ), 7.08 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ),
2
3 2
2
3 2
2
7
8
.23 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6, Í-7), 7.61 (1Í, d, J = 7.6, Í-5), 7.76 (1Í, t, J = 7.6, Í-6), 7.85 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ),
.12–8.18 (2Í, m, NH, Í-8), 12.51 (1Í, br.s, ÑÎÎÍ).
–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}norleucine (11f). C H NO . IR spectrum (ꢃ, cm ): 3379,
2
3
23
6
–1
–1
3
(
084, 2957, 2931, 2871, 2540, 1723, 1632, 1543, 1514, 1290, 1236, 1185, 1071, 831. UV spectrum (ꢄ , nm, ꢅ, Ì ·cm ): 346
13200), 303 (26700), 250 (12500). Í NMR spectrum* (ꢆ, ppm, J/Hz): 0.90 (3Í, m, CH((ÑÍ ) CH )ÑÎÎÍ), 1.27–1.33 (4Í, m,
max
1
2
3
3
CH(ÑÍ (ÑÍ ) CH )ÑÎÎÍ), 1.68 (1Í, m, CH(ÑÍ (ÑÍ ) CH )-ÑÎÎÍ), 1.78 (1Í, m, CH(ÑÍ (ÑÍ ) CH )ÑÎÎÍ), 4.28 (1Í,
2
2 2
3
2
2 2
3
2
2 2
3
m, CH(ÑÍ (ÑÍ ) CH )ÑÎÎÍ), 4.58 (2Í, s, ÑÍ Î-4ꢇ), 7.08 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.23 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6,
2
2 2
3
2
Í-7), 7.62 (1Í, d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.85 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.08 (1Í, br.s, J = 7.6, NH), 8.14 (1Í,
d, J = 7.6, Í-8).
–1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}proline (11g). C H NO . IR spectrum (ꢃ, cm ): 3063, 2984,
22
19
6
2
941, 2890, 1732, 1717, 1670, 1632, 1604, 1515, 1482, 1452, 1432, 1424, 1364, 1346, 1238, 1193, 1077, 827. UV spectrum
–
1
–1
1
(
ꢄmax, nm, ꢅ, Ì ·cm ): 347 (12900), 304 (26000), 251 (11900). Í NMR spectrum (ꢆ, ppm, J/Hz): 1.81–2.24 (4Í, m,
Í-3ꢇꢇ, 4ꢇꢇ), 3.49 (1Í, m, Í -5ꢇꢇ), 3.64 (1Í, m, Í -5ꢇꢇ), 4.54–4.56 (1Í, m, Í-2ꢇꢇ), 4.74–4.85 (2Í, m, ÑÍ Î-4ꢇ), 7.02 (2Í, d, J = 8.4,
ꢁ
ꢂ
2
Í-3ꢇ, 5ꢇ), 7.19 (1Í, s, Í-4), 7.50 (1Í, t, J = 7.6, Í-7), 7.61 (1Í, d, J = 7.6, Í-5), 7.76 (1Í, t, J = 7.6, Í-6), 7.82 (2Í, d, J = 8.4,
Í-2ꢇ, 6ꢇ), 8.14 (1Í, d, J = 7.6, Í-8), 12.46 (1Í, br.s, ÑÎÎÍ).
–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}-ꢂ-alanine (11h). C H NO . IR spectrum (ꢃ, cm ): 3402,
2
0
17
6
3
054, 2910, 2756, 2560, 1732, 1715, 1632, 1610, 1551, 1511, 1285, 1254, 1235, 1176, 1066, 818. UV spectrum (ꢄmax, nm,
–1
–1
1
ꢅ, Ì ·cm ): 346 (13000), 304 (26200), 250 (12400). Í NMR spectrum (ꢆ, ppm, J/Hz): 2.43 (1Í, m, NHCH CH COOH),
2
2
3
.38 (1Í, m, NHCH CH COOH), 4.50 (2Í, s, ÑÍ Î-4ꢇ), 7.06 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.24 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6,
2 2 2
Í-7), 7.62 (1Í, d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.86 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.06 (1Í, br.t, J = 6.4, NH), 8.14 (1Í,
d, J = 7.6, Í-8), 12.11 (1Í, br.s, ÑÎÎÍ).
–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}phenylalanine (11i). C H NO . IR spectrum (ꢃ, cm ):
2
6
21
6
3
387, 3085, 3029, 2940, 2862, 2745, 2531, 1721, 1627, 1546, 1514, 1440, 1246, 1186, 1070, 826. UV spectrum (ꢄmax, nm,
–
1
–1
1
ꢅ, Ì ·cm ): 346 (12000), 303 (24400), 251 (12200). Í NMR spectrum* (ꢆ, ppm, J/Hz): 3.01 (1Í, m, CH(CH Ph)ÑÎÎÍ),
2
3
.12 (1Í, m, CH(CH Ph)ÑÎÎÍ), 4.50–4.58 (3Í, m, CH(CH Ph)ÑÎÎÍ, ÑÍ Î-4ꢇ), 6.98 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.18–7.26
2 2 2
(
6Í, m, CH(CH Ph)ÑÎÎÍ, H-4), 7.51 (1Í, t, J = 7.6, Í-7), 7.62 (1Í, d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.81 (2Í, d,
2
J = 8.4, Í-2ꢇ, 6ꢇ), 8.12–8.16 (2Í, m, NH, Í-8).
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}tryptophan (11j). C H NO . IR spectrum (ꢃ, cm ): 3449,
–
1
2
8
22
6
3
384, 3053, 2930, 2529, 1721, 1636, 1610, 1547, 1513, 1423, 1360, 1236, 1214, 1189, 1075, 829. UV spectrum (ꢄmax, nm,
–1
–1
1
ꢅ, Ì ·cm ): 348 (12700), 304 (25700), 257 (14000). Í NMR spectrum* (ꢆ, ppm, J/Hz): 3.14–3.29 (2Í, m, CH(ÑÎÎÍ)CH ),
2
4
.52 (2Í, s, ÑÍ Î-4ꢇ), 4.58–4.62 (1Í, m, CH(ÑÎÎÍ)CH ), 6.93–6.96 (3Í, m, Í-3ꢇ, 5ꢇ, 5ꢇꢇ), 7.04 (1Í, t, J = 7.2, Í-6ꢇꢇ), 7.09
2
2
(
1Í, br.s, H-2ꢇꢇ), 7.22 (1Í, s, Í-4), 7.33 (1Í, d, J = 7.6, Í-4ꢇꢇ), 7.48–7.56 (2Í, m, Í-7, 7ꢇꢇ), 7.62 (1Í, d, J = 7.6, Í-5), 7.76–
7
.80 (3Í, m, Í-6, 2ꢇ, 6ꢇ), 7.98 (1Í, br.d, J = 7.6, NH), 8.14 (1Í, d, J = 7.6, Í-8), 12.28 (1Í, br.s, 1ꢇꢇ-NH).
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}methionine (11k). C H NO S. IR spectrum (ꢃ, cm ): 3376,
–
1
22
21
6
–
1
–1
3
3
2
086, 2920, 2852, 2522, 1723, 1625, 1546, 1515, 1423, 1253, 1236, 1186, 1071, 830. UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ):
1
45 (13200), 304 (26500), 250 (12900). Í NMR spectrum* (ꢆ, ppm, J/Hz): 1.86–2.06 (5Í, m, CH(ÑÍ ÑÍ SCH )ÑÎÎÍ),
2
2
3
.45 (2Í, m, CH(ÑÍ ÑÍ SCH )ÑÎÎÍ), 4.42 (1Í, m, CH(ÑÍ ÑÍ SCH )ÑÎÎÍ), 4.59 (2Í, s, ÑÍ Î-4ꢇ), 7.08 (2Í, d,
2
2
3
2
2
3
2
J = 8.4, Í-3ꢇ, 5ꢇ), 7.24 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6, Í-7), 7.62 (1Í, d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.86 (2Í,
d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.14 (1Í, d, J = 7.6, Í-8), 8.24 (1Í, br.d, J = 8.0, NH).
641

–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}asparticAcid (11l). C H NO . IR spectrum (ꢃ, cm ): 3429,
21
17
8
–
1
–1
3
3
374, 2927, 2534, 1736, 1720, 1630, 1603, 1514, 1422, 1287, 1238, 1188, 1073, 827. UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ):
1
45 (11700), 304 (23700), 250 (11400). Í NMR spectrum (ꢆ, ppm, J/Hz): 2.73 (2Í, m, ÑÍ(ÑÍ ÑÎÎÍ)ÑÎÎÍ), 4.57–4.68
2
(
(
3Í, m, ÑÍ(ÑÍ ÑÎÎÍ)ÑÎÎÍ, ÑÍ Î-4ꢇ), 7.08 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.24 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6, Í-7), 7.62
1Í, d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.86 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.14 (1Í, d, J = 7.6, Í-8), 8.23 (1Í, br.d, J = 7.2,
2 2
NH), 12.28 (2Í, br.s, ÑÎÎÍ).
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}asparagine (11m). C H N O . IR spectrum (ꢃ, cm ): 3417,
–1
21 18 2 7
3
310, 3227, 2909, 2573, 1727, 1678, 1630, 1605, 1545, 1512, 1420, 1315, 1298, 1263, 1241, 1179, 1073, 826. UV spectrum
–
1
–1
1
(
ꢄmax, nm, ꢅ, Ì ·cm ): 347 (9100), 304 (1850), 250 (8600). Í NMR spectrum* (ꢆ, ppm, J/Hz): 2.60 (1Í, m,
ÑÍ(ÑÍ CONH )ÑÎÎÍ), 2.69 (1Í, m, ÑÍ(ÑÍ CONH )ÑÎÎÍ), 4.56–4.62 (3Í, m, ÑÍ(ÑÍ CONH )ÑÎÎÍ, ÑÍ Î-4ꢇ),
ꢁ
2
ꢂ
2
2
2
2
6
7
.85 (1Í, br.s, CONH ), 7.08 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.24 (1Í, s, Í-4), 7.36 (1Í, br.s, CONH ), 7.50 (1Í, t, J = 7.6, Í-7),
.61 (1Í, d, J = 7.6, Í-5), 7.76 (1Í, t, J = 7.6, Í-6), 7.85 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.14 (1Í, d, J = 7.6, Í-8), 8.26 (1Í, br.d,
2
2
J = 7.6, NH).
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}glutamic Acid (11n). C H NO . IR spectrum (ꢃ, cm ):
–
1
2
2
19
8
3
380, 3081, 2924, 2533, 1727, 1637, 1547, 1514, 1422, 1290, 1254, 1235, 1186, 1070, 825. UV spectrum (ꢄmax, nm,
–
1
–1
1
ꢅ, Ì ·cm ): 347 (12500), 304 (25300), 250 (12000). Í NMR spectrum* (ꢆ, ppm, J/Hz): 1.91 (1Í, m, ÑÍ(ÑÍ ÑÍ COÎÍ)-
ꢁ
2
ÑÎÎÍ), 2.09 (1Í, m, ÑÍ(ÑÍ ÑÍ COÎÍ)ÑÎÎÍ), 2.28 (2Í, m, ÑÍ(ÑÍ ÑÍ COÎÍ)ÑÎÎÍ), 4.31–4.36 (1Í, m,
ꢂ
2
2
2
ÑÍ(ÑÍ ÑÍ COÎÍ)ÑÎÎÍ), 4.59 (2Í, s, ÑÍ Î-4ꢇ), 7.09 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.24 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6,
2
2
2
Í-7), 7.62 (1Í, d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.86 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.14 (1Í, d, J = 7.6, Í-8), 8.24 (1Í,
br.d, J = 7.6, NH).
–
1
N-{[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetyl}citrulline (11o). C H N O . IR spectrum (ꢃ, cm ): 3476,
2
3 23 3 7
–
1
–1
3
389, 3310, 2930, 2880, 1723, 1638, 1513, 1237, 1072, 828. UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ): 346 (12300), 304
1
(
24300), 251 (11500). Í NMR spectrum* (ꢆ, ppm, J/Hz): 1.44 (2Í, m, CH(ÑÍ ÑÍ ÑÍ NHCONH )ÑÎÎÍ), 1.68 (1Í, m,
2
2
2
2
CH(ÑÍ ÑÍ ÑÍ NHCONH )ÑÎÎÍ), 1.81 (1Í, m, CH(ÑÍ ÑÍ ÑÍ NHCONH )ÑÎÎÍ), 3.00 (2Í, m,
ꢁ
2
2
2
ꢂ
2
2
2
CH(ÑÍ ÑÍ ÑÍ NHCONH )-ÑÎÎÍ), 4.30 (1Í, m, CH((ÑÍ ) NHCONH )ÑÎÎÍ), 4.60 (2Í, s, ÑÍ Î-4ꢇ), 5.30 (2Í, br.s,
2
2
2
2
2 3
2
2
NH CONH), 5.95 (1Í, br.s, NH CONH), 7.08 (2Í, d, J = 8.4, Í-3ꢇ, 5ꢇ), 7.25 (1Í, s, Í-4), 7.51 (1Í, t, J = 7.6, Í-7), 7.63 (1Í,
2
2
d, J = 7.6, Í-5), 7.77 (1Í, t, J = 7.6, Í-6), 7.86 (2Í, d, J = 8.4, Í-2ꢇ, 6ꢇ), 8.14 (1Í, d, J = 7.6, Í-8), 8.24 (1Í, br.d, J = 7.2, NH).
–
1
N-{[5-Methyl-2-(1-oxo-1H-isochromen-3-yl)phenoxy]acetyl}glycine (12a). C H NO . IR spectrum (ꢃ, cm ):
2
0
17
6
3
389, 3358, 3328, 2924, 2521, 1740, 1702, 1631, 1561, 1551, 1501, 1483, 1412, 1337, 1220, 1201, 1065, 758, 690.
–
1
–1
1
UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ): 341 (11300), 294 (15900). Í NMR spectrum* (ꢆ, ppm, J/Hz): 2.37 (3Í, s, ÑÍ -5ꢇ),
3
3
.86 (2Í, br.d, J = 4.8, CH ÑÎÎÍ), 4.69 (2Í, s, ÑÍ Î-2ꢇ), 6.99 (1Í, d, J = 8.4, Í-3ꢇ), 7.19 (1Í, br.d, J = 8.4, Í-4ꢇ), 7.53 (1Í,
2 2
t, J = 7.6, Í-7), 7.63–7.67 (3Í, m, Í-4, 5, 6ꢇ), 7.78 (1Í, t, J = 7.6, Í-6), 8.16 (1Í, d, J = 7.6, Í-8), 8.22 (1Í, br.t, J = 4.8, NH).
–
1
N-{[5-Methyl-2-(1-oxo-1H-isochromen-3-yl)phenoxy]acetyl}alanine (12b). C H NO . IR spectrum (ꢃ, cm ):
2
1
19
6
3
388, 2941, 2924, 2611, 2542, 1743, 1727, 1624, 1548, 1500, 1336, 1220, 1149, 1076, 752, 689. UV spectrum (ꢄmax, nm,
–
1
–1
1
ꢅ, Ì ·cm ): 340 (11000), 292 (15500). Í NMR spectrum* (ꢆ, ppm, J/Hz): 1.36 (3Í, d, J = 7.2, CH(CH )ÑÎÎÍ), 2.38 (3Í,
3
s, ÑÍ -5ꢇ), 4.37 (1Í, m, CH(CH )ÑÎÎÍ), 4.62 (2Í, s, ÑÍ Î-2ꢇ), 6.97 (1Í, d, J = 8.4, Í-3ꢇ), 7.19 (1Í, br.d, J = 8.4, Í-4ꢇ), 7.53
3
3
2
(
(
1Í, t, J = 7.6, Í-7), 7.62–7.65 (2Í, m, Í-5, 6ꢇ), 7.68 (1Í, s, Í-4), 7.77 (1Í, t, J = 7.6, Í-6), 8.11 (1Í, br.d, J = 7.6, NH), 8.16
1Í, d, J = 7.6, Í-8).
–
1
N-{[5-Methyl-2-(1-oxo-1H-isochromen-3-yl)phenoxy]acetyl}leucine (12e). C H NO . IR spectrum (ꢃ, cm ):
2
4
25
6
3
404, 3295, 3073, 2959, 2872, 1729, 1663, 1624, 1562, 1503, 1484, 1339, 1259, 1239, 1151, 1072, 759, 690. UV spectrum
–1
–1
1
(
ꢄmax, nm, ꢅ, Ì ·cm ): 342 (10900), 293 (15300). Í NMR spectrum* (ꢆ, ppm, J/Hz): 0.89 (6Í, d, J = 3.2, CH(ÑÍ ÑÍ(CH ) )-
2 3 2
ÑÎÎÍ), 1.55–1.67 (3Í, m, CH(ÑÍ ÑÍ(CH ) )ÑÎÎÍ), 2.38 (3Í, s, ÑÍ -5ꢇ), 4.40 (1Í, m, CH(ÑÍ ÑÍ(CH ) )ÑÎÎÍ), 4.62
2
3 2
3
2
3 2
(
2Í, s, ÑÍ Î-2ꢇ), 6.97 (1Í, d, J = 8.4, Í-3ꢇ), 7.18 (1Í, br.d, J = 8.4, Í-4ꢇ), 7.52 (1Í, t, J = 7.6, Í-7), 7.63–7.65 (3Í, m, Í-4,
2
5
, 6ꢇ), 7.76 (1Í, t, J = 7.6, Í-6), 7.88–7.91 (1Í, m, NH), 8.17 (1Í, d, J = 7.6, Í-8).
N-{[5-Methyl-2-(1-oxo-1H-isochromen-3-yl)phenoxy]acetyl}tryptophan (12j). C H N O . IR spectrum
2
9 24 2 6
–
1
(
(
ꢃ, cm ): 3386, 3332, 3042, 2935, 2617, 2540, 1715, 1631, 1564, 1542, 1502, 1433, 1335, 1233, 1078, 760. UV spectrum
–1
–1
1
ꢄmax, nm, ꢅ, Ì ·cm ): 342 (11400), 291 (19900). Í NMR spectrum (ꢆ, ppm, J/Hz): 2.37 (3Í, s, ÑÍ -5ꢇ), 3.15 (1Í, br.d,
3
J = 14.0, ÑÍ(ÑÎÎÍ)ÑÍ ), 3.28 (1Í, br.d, J = 14.0, ÑÍ(ÑÎÎÍ)ÑÍ ), 4.55–4.68 (3Í, m, ÑÍ Î-2ꢇ, ÑÍ(ÑÎÎÍ)ÑÍ ), 6.91
ꢁ
ꢂ
2
2
(
1Í, t, J = 7.6, Í-5ꢇꢇ), 6.84 (1Í, d, J = 8.4, Í-3ꢇ), 6.99 (1Í, t, J = 7.6, Í-6ꢇꢇ), 7.04 (1Í, br.s, H-2ꢇꢇ), 7.12 (1Í, br.d, J = 8.4,
Í-4ꢇ), 7.25 (1Í, d, J = 7.6, Í-4ꢇꢇ), 7.31 (1Í, d, J = 7.6, Í-7ꢇꢇ), 7.47–7.52 (3Í, m, Í-4, 7, 6ꢇ), 7.56 (2Í, m, Í-5, 6), 8.01 (1Í,
br.d, J = 8.4, NH), 8.12 (1Í, d, J = 7.6, Í-8), 10.68 (1Í, s, 1ꢇꢇ-NH), 12.74 (1Í, br.s, ÑÎÎÍ).
642

N-{[5-Methyl-2-(1-oxo-1H-isochromen-3-yl)phenoxy]acetyl}methionine (12k). C H NO S. IR spectrum
2
3
23
6
–1
(
ꢃ, cm ): 3548, 3490, 3308, 3117, 3076, 3033, 2918, 2608, 1727, 1702, 1659, 1624, 1561, 1553, 1503, 1483, 1439, 1340,
–
1
–1
1
282, 1259, 1239, 1216, 1183, 1150, 1108, 1085, 759, 690. UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ): 340 (10500), 293 (14600).
1
Í NMR spectrum* (ꢆ, ppm, J/Hz): 1.88–2.04 (5Í, m, CH(ÑÍ ÑÍ SCH )ÑÎÎÍ), 2.37 (3Í, s, ÑÍ -5ꢇ), 2.45 (2Í, m,
2
2
3
3
CH(ÑÍ ÑÍ SCH )ÑÎÎÍ), 4.44 (1Í, m, CH(ÑÍ ÑÍ SCH )ÑÎÎÍ), 4.65 (2Í, s, ÑÍ Î-2ꢇ), 6.96 (1Í, d, J = 8.4, Í-3ꢇ), 7.18 (1Í,
2
2
3
2
2
3
2
br.d, J = 8.4, Í-4ꢇ), 7.53 (1Í, t, J = 7.6, Í-7), 7.63–7.66 (2Í, m, Í-5, 6ꢇ), 7.70 (1Í, s, Í-4), 7.78 (1Í, t, J = 7.6, Í-6), 8.15 (1Í,
d, J = 7.6, Í-8), 8.20 (1Í, br.d, J = 6.8, NH).
N-{[5-Methyl-2-(1-oxo-1H-isochromen-3-yl)phenoxy]acetyl}asparagine (12m). C H N O . IR spectrum
2
2 20 2 7
–
1
(
ꢃ, cm ): 3375, 3278, 2923, 2558, 1726, 1702, 1687, 1670, 1622, 1562, 1502, 1438, 1340, 1256, 1240, 1089, 762, 692.
–
1
–1
1
UV spectrum (ꢄmax, nm, ꢅ, Ì ·cm ): 342 (10900), 293 (15100). Í NMR spectrum* (ꢆ, ppm, J/Hz): 2.38 (3Í, s, ÑÍ -5ꢇ),
3
2
.58–2.64 (1Í, m, ÑÍ(ÑÍ CONH )ÑÎÎÍ), 2.67–2.73 (1Í, m, ÑÍ(ÑÍ CONH )ÑÎÎÍ), 4.58–4.72 (3Í, m,
ꢁ 2 ꢂ 2
ÑÍ(ÑÍ CONH )-ÑÎÎÍ, ÑÍ Î-2ꢇ), 6.65 (1Í, br.s, ÑÍ CONH ), 7.00 (1Í, d, J = 8.4, Í-3ꢇ), 7.19 (1Í, br.d, J = 8.4, Í-4ꢇ),
2
2
2
2
ꢁ
7
.27 (1Í, br.s, ÑÍ CONH ), 7.53 (1Í, t, J = 7.6, Í-7), 7.62–7.66 (2Í, m, Í-4, 6ꢇ), 7.72 (1Í, d, J = 7.6, Í-5), 7.76 (1Í, t,
2 ꢂ
J = 7.6, Í-6), 8.15 (2Í, m, Í-8, NH).
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